We propose to produce human monoclonal antibodies (Mabs) to cytomegalovirus (CMV) as a potentially unlimited and safe source of antigen-specific antibodies. We will also analyze their viral antigen specificity and functional effects on the immune response to virus in normal and immunocompromised individuals. While impaired cellular immunity is thought to be the major contributing factor in immunocompromised patients, administration of human plasma with high anti-CMV titers modifies the severity or eliminates CMV infections. The mechanisms whereby antibodies to CMV can modulate infection include neutralization of extracellular virus, complement- mediated lysis of CMV-infected cells, cell-mediated immunity by antibody-dependent cellular cytotoxicity and possible regulatory effects on T cell response to the virus. In this initial phase, the ability to produce human Mabs to CMV has been demonstrated. Of three IgG human anti-CMV Mabs produced, two have been shown to neutralize virus. Preliminary identification has been made of the target molecule of a neutralizing Mab identified within three CMV-associated proteins (MW 46-49,000 60,000 and 140,000). Furthermore, the viral gene epitope recognized by this Mab has tentatively been isolated using a lambda gtll expression system. Lastly, initial studies have shown that human antibodies to CMV will enhance the T cell proliferative response to CMV antigens. Using this approach, the production of a more extensive panel of human Mabs to CMV, particularly of different IgG subclasses, will allow a greater understanding of their specificity and functional effects on CMV and on immune functions of normal and diseased individuals to CMV. The isolation of viral genes encoding CMV-specific proteins identified by these human Mabs will contribute to the development of a recombinant subunit vaccine. Ultimately, these human Mabs should replace human plasma as a source of antibodies in the treatment of CMV infections.